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Local Anesthetics by Brendan Astley MD October 2008.

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1 Local Anesthetics by Brendan Astley MD October 2008

2 Local Anesthetics Used at multiple sites throughout the body: Used at multiple sites throughout the body: Epidural Epidural Spinal Spinal Peripheral nerve blocks Peripheral nerve blocks IV (Bier Block) IV (Bier Block) Skin sites locally Skin sites locally

3 Amides and Esters Chloroprocaine (Nesacaine) Chloroprocaine (Nesacaine) Cocaine (crack) Cocaine (crack) Procaine Procaine Tetracaine (Pontocaine) Tetracaine (Pontocaine) Lidocaine (Xylocaine) Lidocaine (Xylocaine) Bupivacaine (Marcaine) Bupivacaine (Marcaine) Etidocaine (Duranest) Etidocaine (Duranest) Mepivacaine (Carbocaine) Mepivacaine (Carbocaine) Prilocaine (Citanest) Prilocaine (Citanest) Ropivacaine Ropivacaine

4 Mechanism of Action Local anesthetics work in general by binding to sodium channel receptors inside the cell and thereby inhibiting action potentials in a given axon. They work the best when the axon is firing. Local anesthetics work in general by binding to sodium channel receptors inside the cell and thereby inhibiting action potentials in a given axon. They work the best when the axon is firing. The Cell membrane consists of ion pumps, most notably the Na/K pump that create a negative 70mV resting potential by pumping 2 K+ intracellular for every 3 Na+ it pumps extracellular. The Cell membrane consists of ion pumps, most notably the Na/K pump that create a negative 70mV resting potential by pumping 2 K+ intracellular for every 3 Na+ it pumps extracellular.

5 Mechanism of Action (cont’d) If the resting potential encounters the proper chemical, mechanical or electrical stimuli to reduce the membrane potential to less than -55 mV then an action potential is produced that allows the influx of sodium ions. LA act here to block the Na influx. If the resting potential encounters the proper chemical, mechanical or electrical stimuli to reduce the membrane potential to less than -55 mV then an action potential is produced that allows the influx of sodium ions. LA act here to block the Na influx. The influx allows the membrane potential to further increase to +35mV temporarily. The influx allows the membrane potential to further increase to +35mV temporarily. Sodium and potassium channels along with the sodium/potassium pump eventually returning a given axon back to it’s resting membrane potential after an action potential. Sodium and potassium channels along with the sodium/potassium pump eventually returning a given axon back to it’s resting membrane potential after an action potential.

6 Mechanism of Action Benzocaine…. Benzocaine…. Does not exist in a charged form how does it work? Does not exist in a charged form how does it work? Most likely by expanding the lipid membrane of the axon and therefore inhibiting the transport mechanisms of Na and K ions. Most likely by expanding the lipid membrane of the axon and therefore inhibiting the transport mechanisms of Na and K ions.

7 General Structure A lipophilic group…usually a benzene ring A lipophilic group…usually a benzene ring A Hydrophilic group…usually a tertiary amine A Hydrophilic group…usually a tertiary amine These are connected by an intermediate chain that includes an ester or amide linkage These are connected by an intermediate chain that includes an ester or amide linkage LAs are weak bases LAs are weak bases

8 Lipid solubility Most lipid soluble: Most lipid soluble: Tetracaine Tetracaine Bupivicaine Bupivicaine Ropivacaine Ropivacaine Etidocaine Etidocaine Increased lipid solubility also equals greater potency and longer duration of action. Increased lipid solubility also equals greater potency and longer duration of action. Why? Why? Because it has less of a chance of being cleared by blood flow Because it has less of a chance of being cleared by blood flow Decreased lipid solubility means a faster onset of action. Decreased lipid solubility means a faster onset of action. What else effects onset of action??? What else effects onset of action???

9 pKa Local anesthetics with a pKa closest to physiological pH will have a higher concentration of nonionized base that can pass through the nerve cell membrane, and generally a more rapid onset. Local anesthetics with a pKa closest to physiological pH will have a higher concentration of nonionized base that can pass through the nerve cell membrane, and generally a more rapid onset. The charged cation form more avidly binds to the Na+ channel receptors inside the cell membrane. The charged cation form more avidly binds to the Na+ channel receptors inside the cell membrane. pKa > 7.4 more cations, pKa 7.4 more cations, pKa < 7.4 more anions

10 Not all Axons are equal  Motor with fast conduction m/s, diameter 12-20mm, myelinated and not very sensitive to local anesthetic  Motor with fast conduction m/s, diameter 12-20mm, myelinated and not very sensitive to local anesthetic A  - Type Ia and Ib- proprioception fast conduction again m/s, same diameter as above, a little more sensitive to LA, myelinated A  - Type Ia and Ib- proprioception fast conduction again m/s, same diameter as above, a little more sensitive to LA, myelinated A  - Touch pressure and proprioception, smaller diameter 5-12mm and slower conduction 30-70m/s, myelinated and as sensitive to LA as type Ia and Ib fibers A  - Touch pressure and proprioception, smaller diameter 5-12mm and slower conduction 30-70m/s, myelinated and as sensitive to LA as type Ia and Ib fibers

11 Not all Axons are equal A  - motor (muscle spindle) smaller diameter 3-6mm, slower conduction 15-30m/s same LA sensitivity as type Ia and Ib fibers A  - motor (muscle spindle) smaller diameter 3-6mm, slower conduction 15-30m/s same LA sensitivity as type Ia and Ib fibers  - Type III fibers, pain, cold temperature and touch, smaller diameter 2-5mm, 12-30m/s, more sensitive to LA than the above fibers and myelinated.  - Type III fibers, pain, cold temperature and touch, smaller diameter 2-5mm, 12-30m/s, more sensitive to LA than the above fibers and myelinated.

12 Not all Axons are equal B fibers- Preganglionic autonomic fibers, <3mm diameter, 3- 14m/s conduction speed and very sensitive to LA. Some myelination. B fibers- Preganglionic autonomic fibers, <3mm diameter, 3- 14m/s conduction speed and very sensitive to LA. Some myelination. C fibers- Type IV fibers in the dorsal root, pain warm and cold temp. and touch,.4-1.2mm in diameter, slow conduction again at.5-2m/s, very sensitive to LA, not myelinated. C fibers- Type IV fibers in the dorsal root, pain warm and cold temp. and touch,.4-1.2mm in diameter, slow conduction again at.5-2m/s, very sensitive to LA, not myelinated. C fibers- Postganglionic sympathetic fibers, smaller diameters at.3-1.3mm, slow conduction at.7-2.3m/s, very sensitive to LA and no myelination. C fibers- Postganglionic sympathetic fibers, smaller diameters at.3-1.3mm, slow conduction at.7-2.3m/s, very sensitive to LA and no myelination. In general this all means that the autonomic nerves are blocked before the sensory nerves which are blocked before the motor nerves. In general this all means that the autonomic nerves are blocked before the sensory nerves which are blocked before the motor nerves.

13 AMIDES Bupivacaine, Etidocaine and Ropivacaine- very high potency and lipid solubility, very long duration and protein binding also. Bupivacaine, Etidocaine and Ropivacaine- very high potency and lipid solubility, very long duration and protein binding also. Lidocaine, Prilocaine and Mepivacaine- have intermediate potency and lipid solubility and intermediate duration of action and protein binding. Lidocaine, Prilocaine and Mepivacaine- have intermediate potency and lipid solubility and intermediate duration of action and protein binding.

14 ESTERS Chloroprocaine and Procaine- have low potency and lipid solubility and also low duration and protein binding. Chloroprocaine and Procaine- have low potency and lipid solubility and also low duration and protein binding. Cocaine- has intermediate potency and solubility and intermediate duration and protein binding Cocaine- has intermediate potency and solubility and intermediate duration and protein binding Tetracaine- has high potency and lipid solubility along with a long duration of action and high protein binding Tetracaine- has high potency and lipid solubility along with a long duration of action and high protein binding

15 Plasma protein binding What protein are LAs bound??? What protein are LAs bound??? Mostly  1 -acid glycoprotein Mostly  1 -acid glycoprotein To a lesser degree albumin To a lesser degree albumin

16 Absorption Mucous membranes easily absorb LA Mucous membranes easily absorb LA Skin is a different story… Skin is a different story… It requires a high water conc. for penetration and a high lipid concentration for analgesia It requires a high water conc. for penetration and a high lipid concentration for analgesia Which LAs can we use for this? Which LAs can we use for this? EMLA cream- 5% lidocaine and 5% prilocaine in an oil- water emulsion EMLA cream- 5% lidocaine and 5% prilocaine in an oil- water emulsion An occlusive dressing placed for 1 hour will penetrate 3- 5mm and last about 1-2 hours. An occlusive dressing placed for 1 hour will penetrate 3- 5mm and last about 1-2 hours. Typically 1-2 grams of drug per 10cm 2 of skin Typically 1-2 grams of drug per 10cm 2 of skin

17 Rate of systemic absorption Intravenous > tracheal > intercostal > caudal > paracervical > epidural> brachial plexus > sciatic > subcutaneous Intravenous > tracheal > intercostal > caudal > paracervical > epidural> brachial plexus > sciatic > subcutaneous Any vasoconstrictor present?? Any vasoconstrictor present?? High tissue binding also decreases the rate of absorption High tissue binding also decreases the rate of absorption

18 Metabolism Amides… Amides… N-dealkylation and hydroxylation N-dealkylation and hydroxylation P-450 enzymes, liver, slower process than esterase activity P-450 enzymes, liver, slower process than esterase activity Prilocaine>lidocaine>mepivacaine>ropivacaine>bupivacai ne Prilocaine>lidocaine>mepivacaine>ropivacaine>bupivacai ne Prilocaine has a metabolite…. Prilocaine has a metabolite…. o-toluidine o-toluidine This causes methemoglobin to form (Benzocaine can also cause methemoglobin to form) This causes methemoglobin to form (Benzocaine can also cause methemoglobin to form) Treated with methylene blue 1-2mg/kg over 5 minutes Treated with methylene blue 1-2mg/kg over 5 minutes Reduces methemoglobin Fe3+ to hemoglobin Fe2+ Reduces methemoglobin Fe3+ to hemoglobin Fe2+

19 Metabolism Esters… Esters… Pseudocholinesterase Pseudocholinesterase Procaine and benzocaine are metabolized to… Procaine and benzocaine are metabolized to… PABA (p-aminobenzoic acid) allergy risk PABA (p-aminobenzoic acid) allergy risk Tetracaine intrathecal has it’s action terminated by… Tetracaine intrathecal has it’s action terminated by… No esterase activity intrathecally therefore absorption into bloodstream terminates it’s action No esterase activity intrathecally therefore absorption into bloodstream terminates it’s action

20 Clinical Uses Esters Esters Benzocaine- Topical, duration of 30 minutes to 1 hour Benzocaine- Topical, duration of 30 minutes to 1 hour Chloroprocaine- Epidural, infiltration and peripheral nerve block, max dose 12mg/kg, duration 30minutes to 1 hour Chloroprocaine- Epidural, infiltration and peripheral nerve block, max dose 12mg/kg, duration 30minutes to 1 hour Cocaine- Topical, 3mg/kg max., 30 minutes to one hour Cocaine- Topical, 3mg/kg max., 30 minutes to one hour Tetracaine- Spinal, topical, 3mg/kg max., hours duration Tetracaine- Spinal, topical, 3mg/kg max., hours duration

21 Clinical Uses Bupivacaine- Epidural, spinal, infiltration, peripheral nerve block, 3mg/kg max., hours duration Bupivacaine- Epidural, spinal, infiltration, peripheral nerve block, 3mg/kg max., hours duration Lidocaine- Epidural, spinal, infiltration, peripheral nerve block, intravenous regional, topical, 4.5mg/kg or 7mg/kg with epi, hours duration Lidocaine- Epidural, spinal, infiltration, peripheral nerve block, intravenous regional, topical, 4.5mg/kg or 7mg/kg with epi, hours duration Mepivacaine- Epidural, infiltration, peripheral nerve block, 4.5mg/kg or 7mg/kg with epi, 1-2 hours Mepivacaine- Epidural, infiltration, peripheral nerve block, 4.5mg/kg or 7mg/kg with epi, 1-2 hours Prilocaine- Peripheral nerve block (dental), 8mg/kg, 30 minutes to 1 hour duration Prilocaine- Peripheral nerve block (dental), 8mg/kg, 30 minutes to 1 hour duration Ropivacaine- Epidural, spinal, infiltration, peripheral nerve block, 3mg/kg, hours duration Ropivacaine- Epidural, spinal, infiltration, peripheral nerve block, 3mg/kg, hours duration

22 Systemic Toxicity Blockage of voltaged-gated Na channel affects action potential propagation throughout the body…therefore the potential is present for systemic toxicity. Blockage of voltaged-gated Na channel affects action potential propagation throughout the body…therefore the potential is present for systemic toxicity. Mixtures of LA have additive affects Mixtures of LA have additive affects i.e. a 50% toxic dose of lidocaine and a 50% toxic dose of bupivicaine have 100% the toxic affect of either drug i.e. a 50% toxic dose of lidocaine and a 50% toxic dose of bupivicaine have 100% the toxic affect of either drug

23 Systemic Toxicity Neurological Neurological Symptoms include cicumoral numbness, tongue paresthesia, dizziness, tinnitus, blurred vision, restlessness, agitation, nervousness, paranoia, slurred speech, drowsiness, unconsciousness. Symptoms include cicumoral numbness, tongue paresthesia, dizziness, tinnitus, blurred vision, restlessness, agitation, nervousness, paranoia, slurred speech, drowsiness, unconsciousness. Muscle twitching heralds the onset of tonic-clonic seizures with respiratory arrest to follow. Muscle twitching heralds the onset of tonic-clonic seizures with respiratory arrest to follow.

24 Local anesthetic toxicity Seizure treatment: Seizure treatment: Thiopental 1-2mg/kg abruptly terminates seizure activity Thiopental 1-2mg/kg abruptly terminates seizure activity Benzos and hyperventilation…decrease CBF and therefore drug exposure. These raise the threshold of local anesthetic-induced seizures Benzos and hyperventilation…decrease CBF and therefore drug exposure. These raise the threshold of local anesthetic-induced seizures Chloroprocaine injected intrathecally can cause prolonged neurotoxicity. This is likely due to a preservative no longer used with this agent. (Sodium bisulfate) Chloroprocaine injected intrathecally can cause prolonged neurotoxicity. This is likely due to a preservative no longer used with this agent. (Sodium bisulfate)

25 Local anesthetic toxicity Repeated doses of 5% lidocaine and.5% tetracaine may be responsible for cauda equina syndrome following infusion through small bore catheters in spinal anesthetics. Repeated doses of 5% lidocaine and.5% tetracaine may be responsible for cauda equina syndrome following infusion through small bore catheters in spinal anesthetics. Pooling of drug around the cauda equina resulted in permanent neurological damage Pooling of drug around the cauda equina resulted in permanent neurological damage Animal studies suggest that neuro damage is: Lido=tetracaine>bupivacaine>ropivacaine. Also perservative free chloroprocaine may be neurotoxic Animal studies suggest that neuro damage is: Lido=tetracaine>bupivacaine>ropivacaine. Also perservative free chloroprocaine may be neurotoxic

26 Local anesthetic toxicity Transient Neurological Symptoms Transient Neurological Symptoms This is associated with dysethesia, burning pain and aching in lower ext, buttocks. This is associated with dysethesia, burning pain and aching in lower ext, buttocks. Follows spinal anesthesia with variety of agents (lido), attributed to radicular irritation and resolves in 1 week usually Follows spinal anesthesia with variety of agents (lido), attributed to radicular irritation and resolves in 1 week usually Risk factors include Risk factors include Lidocaine intrathecally Lidocaine intrathecally Lithotomy position Lithotomy position Obesity Obesity Outpatient status Outpatient status

27 Local anesthestic toxicity Respiratory center may be depressed (medullary)…postretrobulbar apnea syndrome Respiratory center may be depressed (medullary)…postretrobulbar apnea syndrome Lidocaine depresses hypoxic respiratory drive (PaO2) Lidocaine depresses hypoxic respiratory drive (PaO2) Direct paralysis of phrenic or intercostal nerves Direct paralysis of phrenic or intercostal nerves

28 LA cardio toxicity All LA’s depress spontaneous Phase IV depolarization and reduce the duration of the refractory period All LA’s depress spontaneous Phase IV depolarization and reduce the duration of the refractory period Myocardial contractility and conduction velocity are depressed at higher concentrations Myocardial contractility and conduction velocity are depressed at higher concentrations All LA’s except cocaine cause smooth muscle relaxation and therefore vasodilation (art) whick can lead to brady, heart block and hypotension…cardiac arrest. All LA’s except cocaine cause smooth muscle relaxation and therefore vasodilation (art) whick can lead to brady, heart block and hypotension…cardiac arrest.

29 LA cardio toxicity Major cardiovascular toxicity usually results from 3 times the blood concentration of LA that causes seizures. Major cardiovascular toxicity usually results from 3 times the blood concentration of LA that causes seizures. Therefore cardiac collapse is usually the presenting sign under GA. Therefore cardiac collapse is usually the presenting sign under GA. R isomer of bupivacaine avidly blocks cardiac sodium channels and dissociates very slowly. Making resuscitation prolonged and difficult. R isomer of bupivacaine avidly blocks cardiac sodium channels and dissociates very slowly. Making resuscitation prolonged and difficult.

30 LA cardio toxicity Levo-bupivacaine (S isomer) is no longer avaliable in the US but had a cardiovascular profile similar to ropivacaine. Levo-bupivacaine (S isomer) is no longer avaliable in the US but had a cardiovascular profile similar to ropivacaine. Ropivacaine has a larger therapeutic index and it is 70% less likely to cause severe cardiac dsyrhythmias than bupivacaine Ropivacaine has a larger therapeutic index and it is 70% less likely to cause severe cardiac dsyrhythmias than bupivacaine Also ropviacaine has greater CNS tolerance Also ropviacaine has greater CNS tolerance The improved safety profile is due to a lower lipid solubility The improved safety profile is due to a lower lipid solubility

31 LA toxicity treatment Supportive care: intubation, vasopressors, appropriate defibrillation, fluids, stop injection of LA, anything else…. Supportive care: intubation, vasopressors, appropriate defibrillation, fluids, stop injection of LA, anything else…. Intralipid…Bolus 1cc/kg of 20% intralipid, 0.25cc/kg/min of 20% intralipid for 10 minutes Intralipid…Bolus 1cc/kg of 20% intralipid, 0.25cc/kg/min of 20% intralipid for 10 minutes Bolus can be repeated every 5 minutes up to a maximum of 8cc/kg of 20% intralipid Bolus can be repeated every 5 minutes up to a maximum of 8cc/kg of 20% intralipid Cardiac support should be continued as ACLS dictates Cardiac support should be continued as ACLS dictates Epi and vasopresin should likely both be used in the resusitation efforts (animal model data from A & A) Epi and vasopresin should likely both be used in the resusitation efforts (animal model data from A & A)

32 Lipid, Not Propofol, Treats Bupivacaine Overdose Lipid, Not Propofol, Treats Bupivacaine Overdose Guy Weinberg, MD, Paul Hertz, MD, and Janet Newman, MD Department of Anesthesiology, University of Illinois, Chicago, IL, Guy Weinberg, MD, Paul Hertz, MD, and Janet Newman, MD Department of Anesthesiology, University of Illinois, Chicago, IL, To the Editor: To the Editor: Mayr et al. (1) recently reported the comparative efficacies of epinephrine, vasopressin, and a combination of the two drugs in a porcine model of bupivacaine overdose. They used a single 5 mg/kg IV bolus of bupivacaine, applied advanced cardiac life support 1 min after asystole, and administered drugs 2 min later and at 5-min intervals thereafter. Monophasic countershocks were applied as dictated by rhythm disturbance. Rates of survival were 5/7 for vasopressin, 4/7 for epinephrine, 7/7 in the combined treatment group, and 0/7 in controls. Mayr et al. (1) recently reported the comparative efficacies of epinephrine, vasopressin, and a combination of the two drugs in a porcine model of bupivacaine overdose. They used a single 5 mg/kg IV bolus of bupivacaine, applied advanced cardiac life support 1 min after asystole, and administered drugs 2 min later and at 5-min intervals thereafter. Monophasic countershocks were applied as dictated by rhythm disturbance. Rates of survival were 5/7 for vasopressin, 4/7 for epinephrine, 7/7 in the combined treatment group, and 0/7 in controls.(1) By comparison, we reported that injecting a 20% lipid emulsion in combination with cardiac massage leads to successful return of normal hemodynamics in 9/9 dogs after a bolus injection of 10 mg/kg bupivacaine (2). Lipid infusion in 6 of these dogs was delayed for 10 min to approximate a clinical scenario. A normal rhythm was established in all 9 dogs within 5 min; no electrical counter shock was required. No control animal demonstrated return of BP or HR. By comparison, we reported that injecting a 20% lipid emulsion in combination with cardiac massage leads to successful return of normal hemodynamics in 9/9 dogs after a bolus injection of 10 mg/kg bupivacaine (2). Lipid infusion in 6 of these dogs was delayed for 10 min to approximate a clinical scenario. A normal rhythm was established in all 9 dogs within 5 min; no electrical counter shock was required. No control animal demonstrated return of BP or HR.(2) Dogs and pigs may differ in terms of susceptibility to bupivacaine cardiac toxicity; the porcine and canine models may not be completely comparable for this and other reasons. However, we and others (3) believe the rapid return of normal rhythm and hemodynamics in both dogs and rats following massive bupivacaine overdose (twice the dose used in Mayr’s study), indicates superior efficacy of lipid rescue for bupivacaine toxicity to drugs, such as epinephrine and vasopressin that are components of the generic ACLS protocol for cardiopulmonary arrest (4). Perhaps Dr. Mayr will consider comparing combined epinephrine/vasopressin with lipid rescue in the porcine model of bupivacaine cardiac toxicity. Dogs and pigs may differ in terms of susceptibility to bupivacaine cardiac toxicity; the porcine and canine models may not be completely comparable for this and other reasons. However, we and others (3) believe the rapid return of normal rhythm and hemodynamics in both dogs and rats following massive bupivacaine overdose (twice the dose used in Mayr’s study), indicates superior efficacy of lipid rescue for bupivacaine toxicity to drugs, such as epinephrine and vasopressin that are components of the generic ACLS protocol for cardiopulmonary arrest (4). Perhaps Dr. Mayr will consider comparing combined epinephrine/vasopressin with lipid rescue in the porcine model of bupivacaine cardiac toxicity.(3)(4)(3)(4) Mayr et al. (1) also incorrectly cite us as indicating that "....a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and, therefore, this strategy has been suggested as a potential means to improve outcomes from such toxicity." We have never recommended use of propofol for treating bupivacaine overdose, and strongly suspect that its use in cardiac arrest will impede resuscitation. Mayr et al. (1) also incorrectly cite us as indicating that "....a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and, therefore, this strategy has been suggested as a potential means to improve outcomes from such toxicity." We have never recommended use of propofol for treating bupivacaine overdose, and strongly suspect that its use in cardiac arrest will impede resuscitation.(1) We have recommended treating bupivacaine-associated cardiac arrest by injecting a 1 mL/kg bolus of 20% lipid emulsion (such as Intralipid) and starting an infusion of 0.25 mL/kg/min for 10 min, while continuing basic life support (5). The bolus could be repeated every 5 min, two or three times if needed. The upper dose limit of 20% lipid emulsion is not known, but a total of more than 8 mL/kg is not likely to be needed, nor successful if lower doses are not. Note that this protocol will deliver a significant volume load (several hundred mL in an adult). The standard formulation of propofol is 10% lipid and 1% propofol. Therefore, gram quantities of propofol would accompany our recommended regimen and only half the dose of lipid, the necessary ingredient, would be delivered. We have recommended treating bupivacaine-associated cardiac arrest by injecting a 1 mL/kg bolus of 20% lipid emulsion (such as Intralipid) and starting an infusion of 0.25 mL/kg/min for 10 min, while continuing basic life support (5). The bolus could be repeated every 5 min, two or three times if needed. The upper dose limit of 20% lipid emulsion is not known, but a total of more than 8 mL/kg is not likely to be needed, nor successful if lower doses are not. Note that this protocol will deliver a significant volume load (several hundred mL in an adult). The standard formulation of propofol is 10% lipid and 1% propofol. Therefore, gram quantities of propofol would accompany our recommended regimen and only half the dose of lipid, the necessary ingredient, would be delivered.(5) Propofol is not an acceptable treatment for bupivacaine overdose. Propofol is not an acceptable treatment for bupivacaine overdose. References References Mayr VD, Raedler C, Wenzel V, et al. A comparison of epinephrine and vasopressin in a porcine model of cardiac arrest after rapid intravenous injection of bupivacaine. Anesth Analg 2004; 98: 1426–31.[Abstract/Free Full Text] Mayr VD, Raedler C, Wenzel V, et al. A comparison of epinephrine and vasopressin in a porcine model of cardiac arrest after rapid intravenous injection of bupivacaine. Anesth Analg 2004; 98: 1426–31.[Abstract/Free Full Text][Abstract/Free Full Text] Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003; 28: 198– 202.[ISI][Medline] Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003; 28: 198– 202.[ISI][Medline][ISI][Medline][ISI][Medline] Groban L, Butterworth J. Lipid reversal of bupivacaine toxicity: has the silver bullet been identified? Reg Anesth Pain Med 2003; 28: 167–9.[ISI][Medline] Groban L, Butterworth J. Lipid reversal of bupivacaine toxicity: has the silver bullet been identified? Reg Anesth Pain Med 2003; 28: 167–9.[ISI][Medline][ISI][Medline][ISI][Medline] Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: advanced challenges in resuscitation: section 2: toxicology in ECC. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000; 102 (suppl 8): I223–8.[Medline] Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: advanced challenges in resuscitation: section 2: toxicology in ECC. The American Heart Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000; 102 (suppl 8): I223–8.[Medline][Medline] Weinberg G. Lipid rescue: caveats and recommendations for the "Silver Bullet" [letter]. Reg Anesth Pain Med 2004; 29: 74–5. Weinberg G. Lipid rescue: caveats and recommendations for the "Silver Bullet" [letter]. Reg Anesth Pain Med 2004; 29: 74–5. Response Response Viktoria D. Mayr, MD, Claus Raedler, MD, Volker Wenzel, MD, Karl H. Lindner, MD, and Hans-Ulrich Strohmenger, MD Univ. Klinik f. Anaesthesie u. Allg. Intensivmedezin, Innsbruck, Austria, Viktoria D. Mayr, MD, Claus Raedler, MD, Volker Wenzel, MD, Karl H. Lindner, MD, and Hans-Ulrich Strohmenger, MD Univ. Klinik f. Anaesthesie u. Allg. Intensivmedezin, Innsbruck, Austria, In Response: In Response: We would like to thank Weinberg et al. for their interest in our work, as well as for their constructive comments. First, we sincerely apologize for having incorrectly cited Weinberg et al. by confounding propofol and intralipid; we completely agree with their statement that propofol administration cannot be recommended for managing a bupivacaine overdose. When indicating in the Discussion section that "... a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and therefore, this strategy has been suggested as a potential means to improve outcomes from such toxicity," we did not suggest to use propofol for treating bupivacaine toxicity, nor that Dr. Weinberg et al. used propofol for treating bupivacaine toxicity. We share the same opinion that usage of propofol in cardiac arrest may impede resuscitation. With our statement about a "lipid infusion such as propofol...", we only wanted to state the reason why we did not use propofol but isoflurane and nitrous oxide to maintain anesthesia in our experiment. Instead of saying "... a lipid infusion such as propofol...", it would have been better to state "... as propofol is a lipid infusion which may increase the dose of bupivacaine required to induce cardiac arrest..." Second, beneficial lipid effects during massive bupivacaine overdose as described by Weinberg et al. resulted in impressive outcome data. However, their conclusion drawn in the letter that these results indicate the superiority of this treatment regime in comparison to advanced cardiac life support including epinephrine and vasopressin has not been proven. The comparative investigation of the epinephrine/vasopressin combination and the lipid rescue protocol in the same animal model of bupivacaine cardiac toxicity can only provide reliable information in this respect. We would like to thank Weinberg et al. for their interest in our work, as well as for their constructive comments. First, we sincerely apologize for having incorrectly cited Weinberg et al. by confounding propofol and intralipid; we completely agree with their statement that propofol administration cannot be recommended for managing a bupivacaine overdose. When indicating in the Discussion section that "... a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and therefore, this strategy has been suggested as a potential means to improve outcomes from such toxicity," we did not suggest to use propofol for treating bupivacaine toxicity, nor that Dr. Weinberg et al. used propofol for treating bupivacaine toxicity. We share the same opinion that usage of propofol in cardiac arrest may impede resuscitation. With our statement about a "lipid infusion such as propofol...", we only wanted to state the reason why we did not use propofol but isoflurane and nitrous oxide to maintain anesthesia in our experiment. Instead of saying "... a lipid infusion such as propofol...", it would have been better to state "... as propofol is a lipid infusion which may increase the dose of bupivacaine required to induce cardiac arrest..." Second, beneficial lipid effects during massive bupivacaine overdose as described by Weinberg et al. resulted in impressive outcome data. However, their conclusion drawn in the letter that these results indicate the superiority of this treatment regime in comparison to advanced cardiac life support including epinephrine and vasopressin has not been proven. The comparative investigation of the epinephrine/vasopressin combination and the lipid rescue protocol in the same animal model of bupivacaine cardiac toxicity can only provide reliable information in this respect.

33 True Allergic Reactions to LA’s Very uncommon Very uncommon Esters more likely because of p-aminobenzoic acid (allergen) Esters more likely because of p-aminobenzoic acid (allergen) Methylparaben preservative present in amides is also a known allergen Methylparaben preservative present in amides is also a known allergen

34 Local Anesthetic Musculoskeletal Cause myonecrosis when injected directly into the muscle Cause myonecrosis when injected directly into the muscle When steroid or epi added the myonecrosis is worsened When steroid or epi added the myonecrosis is worsened Regeneration usually takes 3-4 weeks Regeneration usually takes 3-4 weeks Ropivacaine produces less sereve muscle injury than bupivacaine Ropivacaine produces less sereve muscle injury than bupivacaine

35 Drug Interactions Chloroprocaine epidurally may interfere with the analgesic effects of intrathecal morphine Chloroprocaine epidurally may interfere with the analgesic effects of intrathecal morphine Opioids and  2 agonists potentiate LA’s Opioids and  2 agonists potentiate LA’s Propranolol and cimetidine decrease hepatic blood flow and decrease lidocaine clearance Propranolol and cimetidine decrease hepatic blood flow and decrease lidocaine clearance Pseudocholinesterase inhibitors decrease Ester LA metabolism Pseudocholinesterase inhibitors decrease Ester LA metabolism Dibucaine (amide LA) inhibits pseudocholinesterase used to detect abn enzyme Dibucaine (amide LA) inhibits pseudocholinesterase used to detect abn enzyme Sux and ester LA need pseudochol. for metabolism therefore adminstering both may potentiate their activity Sux and ester LA need pseudochol. for metabolism therefore adminstering both may potentiate their activity LA potentiate nondepolarizing muscle relaxant blockade LA potentiate nondepolarizing muscle relaxant blockade

36 Other agents with LA properties Meperidine Meperidine TCAs (amitriptyline) TCAs (amitriptyline) Volatile anesthetics Volatile anesthetics Ketamine Ketamine Tetrodotoxin (blocks Na channels from the outside of the cell membrane) Animal studies suggest that when used in low doses with vasoconstrictors it will significantly prolong duration of action of LA. Tetrodotoxin (blocks Na channels from the outside of the cell membrane) Animal studies suggest that when used in low doses with vasoconstrictors it will significantly prolong duration of action of LA.

37 Bibliography Clinical Anesthesiology, Morgan and Mikhail Clinical Anesthesiology, Morgan and Mikhail


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